title: Effects of phosphodiesterase 4 inhibition on alveolarization and hyperoxia toxicity in newborn rats.
abstract: BACKGROUND
  Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury.
  
  
  RESULTS
  Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count.
  
  
  CONCLUSIONS
  Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.
authors.affiliation: Institut National de la Santé et de la Recherche médicale U767, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Méhats
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Franco-Montoya
authors.forename: Olivier
authors.initials: O
authors.lastname: Boucherat
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lopez
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitz
authors.forename: Elodie
authors.initials: E
authors.lastname: Zana
authors.forename: Danièle
authors.initials: D
authors.lastname: Evain-Brion
authors.forename: Jacques
authors.initials: J
authors.lastname: Bourbon
authors.forename: Christophe
authors.initials: C
authors.lastname: Delacourt
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Jarreau
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018496:Hyperoxia / Q000150:complications* / Q000401:mortality / Q000473:pathology; D007249:Inflammation; D055370:Lung Injury / Q000209:etiology*; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000254:growth & development*; D051381:Rats; D020889:Rolipram / Q000494:pharmacology*; D015430:Weight Gain
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D020889:Rolipram